Grant: Project Grant

Our objective is to better understand the initial processes that lead to Alzheimer's disease (AD), a neurodegenerative condition that evolves silently for decades before it can be clinically diagnosed using current methods. Identify molecules implicated in the development of an evolving 'silent' AD pathology is crucial, as such early pre-symptomatic stages are likely more responsive to therapy than treatment during symptomatic AD stages when the brain has already suffered extensive and irreversible damage. In the pursuit of this objective, we will focus our studies on early CNS inflammatory processes that we have shown to occur well before amyloid plaques are established; this early inflammation is different from classical late CNS inflammation that responds to toxic amyloid plaque formation. While late inflammation serves to removes toxic proteins and involves an immunological reaction, we have shown that early inflammation is a disease-aggravating process, amenable to treatment. Using animal models with modified brain genes to reproduce key features of the human AD pathology, we will examine which types of brain cells exhibit the first signs of inflammation and when this process begins. Further, we will investigate the presence of early inflammation in post-mortem human brain tissue from healthy individuals and individuals at different stages of AD to determine how inflammation coincides with the presence of other early AD hallmarks and cognitive status. Finally, we will determine how inflammation changes with time and disease progression in blood and cerebrospinal fluid of people at high risk of developing the disease, such as individuals with a family history of AD and Down syndrome sufferers. Studying the earliest occurrence of amyloid-driven inflammation may reveal a critical therapeutic window, whereby attenuating these initial processes would protect against brain dysfunction and consequential cognitive decline.